A Neurovascular Perspective for Long-Term Changes After Brain Trauma

Wade SL, Michaud L, Brown TM. Putting the pieces together: preliminary efficacy of a family problem-solving intervention for children with traumatic brain injury. J Head Trauma Rehab. 2006;21(1):57–67. Brancu M, Straits-Troster K, Kudler H. Behavioral health conditions among military personnel and veterans: prevalence and best practices for treatment. N C Med J. 2011;72(1):54–60. Faul M et al. Traumatic brain injury in the United States: emergency department visits, hospitalizations, and deaths, 2002–2006. Atlanta: CDC; 2010. Zaloshnja E et al. Prevalence of long-term disability from traumatic brain injury in the civilian population of the United States, 2005. J Head Trauma Rehab. 2008;23(6):394–400. Selassie AW et al. Incidence of long-term disability following traumatic brain injury hospitalization, United States, 2003. J Head Trauma Rehab. 2008;23(2):123–31. Thurman D, Guerrero J. Trends in hospitalization associated with traumatic brain injury. JAMA. 1999;282(10):954–7. Thurman DJ et al. Traumatic brain injury in the United States: a public health perspective. J Head Trauma Rehab. 1999;14(6):602–15. Langlois JA, Rutland-Brown W, Wald MM. The epidemiology and impact of traumatic brain injury: a brief overview. J Head Trauma Rehab. 2006;21(5):375–8. Coronado VG et al. Surveillance for traumatic brain injury-related deaths—United States, 1997–2007. MMWR Surveill Summ. 2011;60(5):1–32. Finkelstein E et al. The incidence and economic burden of injuries in the United States. New York: Oxford University Press; 2006. Vakili A, Kataoka H, Plesnila N. Role of arginine vasopressin V1 and V2 receptors for brain damage after transient focal cerebral ischemia. J Cereb Blood Flow Metab. 2005;25(8):1012–9. Trabold R et al. Role of vasopressin V(1a) and V2 receptors for the development of secondary brain damage after traumatic brain injury in mice. J Neurotraum. 2008;25(12):1459–65. Smith DH et al. Protein accumulation in traumatic brain injury. Neuromol Med. 2003;4(1–2):59–72. Gavett BE et al. Mild traumatic brain injury: a risk factor for neurodegeneration. Alzheimers Res Ther. 2010;2(3):18. Johnson VE, Stewart W, Smith DH. Traumatic brain injury and amyloid-beta pathology: a link to Alzheimer’s disease? Nat Rev Neurosci. 2010;11(5):361–70. Maas AI, Stocchetti N, Bullock R. Moderate and severe traumatic brain injury in adults. Lancet Neurol. 2008;7(8):728–41. Malec JF et al. The mayo classification system for traumatic brain injury severity. J Neurotraum. 2007;24(9):1417–24. Ponsford J et al. Cognitive and behavioral outcome following mild traumatic head injury in children. J Head Trauma Rehab. 1999;14(4):360–72. Ponsford J et al. Impact of early intervention on outcome after mild traumatic brain injury in children. Pediatrics. 2001;108(6):1297–303. Ponsford J et al. Long-term outcomes after uncomplicated mild traumatic brain injury: a comparison with trauma controls. J Neurotraum. 2011;28(6):937–46. Lippert-Gruner M et al. Neurobehavioural deficits after severe traumatic brain injury (TBI). Brain Inj. 2006;20(6):569–74. Kuppermann N et al. Identification of children at very low risk of clinically-important brain injuries after head trauma: a prospective cohort study. Lancet. 2009;374(9696):1160–70. Schneier AJ et al. Incidence of pediatric traumatic brain injury and associated hospital resource utilization in the United States. Pediatrics. 2006;118(2):483–92. Brown AW et al. Long-term survival after traumatic brain injury: a population-based analysis. NeuroRehabilitation. 2004;19(1):37–43. Harrison-Felix C et al. Mortality following rehabilitation in the traumatic brain injury model systems of care. NeuroRehabilitation. 2004;19(1):45–54. Himanen L et al. Risk factors for reduced survival after traumatic brain injury: a 30-year follow-up study. Brain Inj. 2011;25(5):443–52. Anderson V et al. Educational, vocational, psychosocial, and quality-of-life outcomes for adult survivors of childhood traumatic brain injury. J Head Trauma Rehab. 2009;24(5):303–12. Anderson V et al. Intellectual outcome from preschool traumatic brain injury: a 5-year prospective, longitudinal study. Pediatrics. 2009;124(6):e1064–71. Babikian T, Asarnow R. Neurocognitive outcomes and recovery after pediatric TBI: meta-analytic review of the literature. Neuropsychology. 2009;23(3):283–96. Babikian T et al. The UCLA longitudinal study of neurocognitive outcomes following mild pediatric traumatic brain injury. J Int Neuropsychol Soc. 2011;17:886–95. Levin HS et al. Magnetic resonance imaging and computerized tomography in relation to the neurobehavioral sequelae of mild and moderate head injuries. J Neurosurg. 1987;66(5):706–13. Fujii D, Ahmed I. Psychotic disorder following traumatic brain injury: a conceptual framework. Cogn Neuropsychiatry. 2002;7(1):41–62. Giza CC. Lasting effects of pediatric traumatic brain injury. Indian J Neurotraum. 2006;3(1):19–26. Satz P. Brain reserve capacity on symptom onset after brain injury: a formulation and review of evidence for threshold theory. Neuropsychology. 1993;7(3):273–95. Ikonomovic MD et al. Alzheimer’s pathology in human temporal cortex surgically excised after severe brain injury. Exp Neurol. 2004;190(1):192–203. DeKosky ST et al. Association of increased cortical soluble abeta42 levels with diffuse plaques after severe brain injury in humans. Arch Neurol. 2007;64(4):541–4. Levine B et al. The Toronto traumatic brain injury study: injury severity and quantified MRI. Neurology. 2008;70(10):771–8. McKee AC et al. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol. 2009;68(7):709–35. Baethmann A et al. Mediators of brain edema and secondary brain damage. Crit Care Med. 1988;16(10):972–8. Sahuquillo J, Poca MA, Amoros S. Current aspects of pathophysiology and cell dysfunction after severe head injury. Curr Pharm Des. 2001;7(15):1475–503. Gaetz M. The neurophysiology of brain injury. Clin Neurophysiol. 2004;115(1):4–18. Zweckberger K et al. Effect of early and delayed decompressive craniectomy on secondary brain damage after controlled cortical impact in mice. J Neurotraum. 2006;23(7):1083–93. Bell RD, Zlokovic BV. Neurovascular mechanisms and blood–brain barrier disorder in Alzheimer’s disease. Acta Neuropathol. 2009;118(1):103–13. Iadecola C, Nedergaard M. Glial regulation of the cerebral microvasculature. Nat Neurosci. 2007;10(11):1369–76. Neuwelt EA et al. Engaging neuroscience to advance translational research in brain barrier biology. Nat Rev Neurosci. 2011;12(3):169–82. Engelhardt B, Coisne C. Fluids and barriers of the CNS establish immune privilege by confining immune surveillance to a two-walled castle moat surrounding the CNS castle. Fluids Barriers CNS. 2011;8(1):4. Saunders NR, Knott GW, Dziegielewska KM. Barriers in the immature brain. Cell Mol Neurobiol. 2000;20(1):29–40. Saunders NR et al. Barriers in the brain: a renaissance? Trends Neurosci. 2008;31(6):279–86. Abbott NJ, Ronnback L, Hansson E. Astrocyte–endothelial interactions at the blood–brain barrier. Nat Rev Neurosci. 2006;7(1):41–53. Abbott NJ et al. Structure and function of the blood–brain barrier. Neurobiol Dis. 2010;37(1):13–25. Owens T, Bechmann I, Engelhardt B. Perivascular spaces and the two steps to neuroinflammation. J Neuropathol Exp Neurol. 2008;67(12):1113–21. Tam SJ, Watts RJ. Connecting vascular and nervous system development: angiogenesis and the blood–brain barrier. Annu Rev Neurosci. 2010;33:379–408. Daneman R et al. Pericytes are required for blood–brain barrier integrity during embryogenesis. Nature. 2010;468(7323):562–6. Armulik A et al. Pericytes regulate the blood–brain barrier. Nature. 2010;468(7323):557–61. Bushong EA, Martone ME, Ellisman MH. Maturation of astrocyte morphology and the establishment of astrocyte domains during postnatal hippocampal development. Int J Dev Neurosci. 2004;22(2):73–86. Silverberg GD et al. Amyloid efflux transporter expression at the blood–brain barrier declines in normal aging. J Neuropathol Exp Neurol. 2010;69(10):1034–43. Silverberg GD et al. Amyloid and tau accumulate in the brains of aged hydrocephalic rats. Brain Res. 2010;1317:286–96. Werner C, Engelhard K. Pathophysiology of traumatic brain injury. Br J Anaesth. 2007;99(1):4–9. Bouma GJ et al. Cerebral circulation and metabolism after severe traumatic brain injury: the elusive role of ischemia. J Neurosurg. 1991;75(5):685–93. Bryan Jr RM, Cherian L, Robertson C. Regional cerebral blood flow after controlled cortical impact injury in rats. Anesth Analg. 1995;80(4):687–95. Engel DC et al. Changes of cerebral blood flow during the secondary expansion of a cortical contusion assessed by 14C-iodoantipyrine autoradiography in mice using a non-invasive protocol. J Neurotraum. 2008;25(7):739–53. Kochanek PM et al. Severe controlled cortical impact in rats: assessment of cerebral edema, blood flow, and contusion volume. J Neurotraum. 1995;12(6):1015–25. Schroder ML et al. Focal ischemia due to traumatic contusions documented by stable xenon-CT and ultrastructural studies. J Neurosurg. 1995;82(6):966–71. Sahuquillo J et al. Evaluation of cerebrovascular CO2-reactivity and autoregulation in patients with post-traumatic diffuse brain swelling (diffuse injury III). Act Neur S. 1998;71:233–6. Vavilala MS et al. Impaired cerebral autoregulation and 6-month outcome in children with severe traumatic brain injury: preliminary findings. Dev Neurosci. 2006;28(4–5):348–53. Muizelaar JP et al. Cerebral blood flow and metabolism in severely head-injured children. Part 1: relationship with GCS score, outcome, ICP, and PVI. J Neurosurg. 1989;71(1):63–71. Muizelaar JP et al. Cerebral blood flow and metabolism in severely head-injured children. Part 2: autoregulation. J Neurosurg. 1989;71(1):72–6. Freeman SS et al. Young age as a risk factor for impaired cerebral autoregulation after moderate to severe pediatric traumatic brain injury. Anesthesiology. 2008;108(4):588–95. Sharples PM, Matthews DS, Eyre JA. Cerebral blood flow and metabolism in children with severe head injuries. Part 2: cerebrovascular resistance and its determinants. J Neurol Neurosurg Psychiatry. 1995;58(2):153–9. Sharples PM et al. Cerebral blood flow and metabolism in children with severe head injury. Part 1: relation to age, Glasgow coma score, outcome, intracranial pressure, and time after injury. J Neurol Neurosurg Psychiatry. 1995;58(2):145–52. Armstead WM. Cerebral hemodynamics after traumatic brain injury of immature brain. Exp Toxicol Pathol. 1999;51(2):137–42. Armstead WM. Role of endothelin-1 in age-dependent cerebrovascular hypotensive responses after brain injury. Am J Physiol. 1999;277(5 Pt 2):H1884–94. Armstead WM. Age-dependent impairment of K(ATP) channel function following brain injury. J Neurotraum. 1999;16(5):391–402. Armstead WM. Stimulus duration modulates the interaction between opioids and nitric oxide in hypoxic pial artery dilation. Brain Res. 1999;825(1–2):68–74. Armstead WM. Superoxide generation links protein kinase C activation to impaired ATP-sensitive K+ channel function after brain injury. Stroke. 1999;30(1):153–9. Hamel E. Perivascular nerves and the regulation of cerebrovascular tone. J Appl Physiol. 2006;100(3):1059–64. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288(5789):373–6. Wada K et al. Role of nitric oxide in traumatic brain injury in the rat. J Neurosurg. 1998;89(5):807–18. Cherian L, Hlatky R, Robertson CS. Nitric oxide in traumatic brain injury. Brain Pathol. 2004;14(2):195–201. Armstead WM et al. Glucagon protects against impaired NMDA-mediated cerebrovasodilation and cerebral autoregulation during hypotension after brain injury by activating cAMP protein kinase A and inhibiting upregulation of tPA. J Neurotraum. 2011;28(3):451–7. Cherian L, Robertson CS. l-arginine and free radical scavengers increase cerebral blood flow and brain tissue nitric oxide concentrations after controlled cortical impact injury in rats. J Neurotraum. 2003;20(1):77–85. Orihara Y et al. Induction of nitric oxide synthase by traumatic brain injury. Forensic Sci Int. 2001;123(2–3):142–9. Steiner J et al. Attenuation of iNOS mRNA exacerbates hypoperfusion and upregulates endothelin-1 expression in hippocampus and cortex after brain trauma. Nato Sci S A Lif Sci. 2004;10(3):162–9. Xia Y, Zweier JL. Superoxide and peroxynitrite generation from inducible nitric oxide synthase in macrophages. Proc Natl Acad Sci USA. 1997;94(13):6954–8. Xia Y et al. Inducible nitric-oxide synthase generates superoxide from the reductase domain. J Biol Chem. 1998;273(35):22635–9. Guix FX et al. The physiology and pathophysiology of nitric oxide in the brain. Prog Neurobiol. 2005;76(2):126–52. Armstead WM et al. Phenylephrine infusion prevents impairment of ATP- and calcium-sensitive potassium channel-mediated cerebrovasodilation after brain injury in female, but aggravates impairment in male, piglets through modulation of ERK MAPK upregulation. J Neurotraum. 2011;28(1):105–11. Plesnila N et al. Relative cerebral blood flow during the secondary expansion of a cortical lesion in rats. Neurosci Lett. 2003;345(2):85–8. Ashwal S et al. Predictive value of proton magnetic resonance spectroscopy in pediatric closed head injury. Pediatr Neurol. 2000;23(2):114–25. Bartnik BL, Spigelman I, Obenaus A. Cell-permeant calcium buffer induced neuroprotection after cortical devascularization. Exp Neurol. 2005;192(2):357–64. Bartnik BL et al. Upregulation of pentose phosphate pathway and preservation of tricarboxylic acid cycle flux after experimental brain injury. J Neurotraum. 2005;22(10):1052–65. Casey PA et al. Early and sustained alterations in cerebral metabolism after traumatic brain injury in immature rats. J Neurotraum. 2008;25(6):603–14. Ashwal S et al. Proton spectroscopy detected myoinositol in children with traumatic brain injury. Pediatr Res. 2004;56(4):630–8. Rhodes J. Peripheral immune cells in the pathology of traumatic brain injury? Curr Opin Crit Care. 2011;17(2):122–30. Badaut J, Ashwal S, Obenaus A. Aquaporins in cerebrovascular disease: a target for treatment of brain edema? Cerebrovasc Dis. 2011;31(6):521–31. Unterberg AW et al. Edema and brain trauma. Neuroscience. 2004;129(4):1021–9. Klatzo I. Brain oedema following brain ischaemia and the influence of therapy. Br J Anaesth. 1985;57(1):18–22. Pappius HM. Part I: tumors of the brain and skull. In: Vinken PJ, Bruyn GW, editors. Handbook of clinical neurology. New York: North Holland Publishing Company; 1974. p. 167–85. Bauer R, Fritz H. Pathophysiology of traumatic injury in the developing brain: an introduction and short update. Exp Toxicol Pathol. 2004;56(1–2):65–73. Lang DA et al. Diffuse brain swelling after head injury: more often malignant in adults than children? J Neurosurg. 1994;80(4):675–80. Kochanek PM. Pediatric traumatic brain injury: quo vadis? Dev Neurosci. 2006;28(4–5):244–55. Wen H et al. Ontogeny of water transport in rat brain: postnatal expression of the aquaporin-4 water channel. Eur J Neurosci. 1999;11(3):935–45. Dobbing J. The later development of the brain and its vulnerability. In: Davis JA, Dobbing J, editors. Scientific foundations of paediatrics. London: Heinemann; 1981. p. 744–59. Badaut J, Regli L. Distribution and possible roles of aquaporin 9 in the brain. Neuroscience. 2004;129(4):971–81. Badaut J et al. Aquaporin 1 and aquaporin 4 expression in human brain after subarachnoid hemorrhage and in peritumoral tissue. Act Neur S. 2003;86:495–8. Badaut J et al. Aquaporins in brain: distribution, physiology, and pathophysiology. J Cereb Blood Flow Metab. 2002;22(4):367–78. de Castro Ribeiro M et al. Thrombin in ischemic neuronal death. Exp Neurol. 2006;198(1):199–203. Badaut J. Aquaglyceroporin 9 in brain pathologies. Neuroscience. 2010;168(4):1047–57. Neuwelt E et al. Strategies to advance translational research into brain barriers. Lancet Neurol. 2008;7(1):84–96. Ke C et al. Heterogeneous responses of aquaporin-4 in oedema formation in a replicated severe traumatic brain injury model in rats. Neurosci Lett. 2001;301(1):21–4. Kiening KL et al. Decreased hemispheric aquaporin-4 is linked to evolving brain edema following controlled cortical impact injury in rats. Neurosci Lett. 2002;324(2):105–8. Sun MC et al. Regulation of aquaporin-4 in a traumatic brain injury model in rats. J Neurosurg. 2003;98(3):565–9. Meng S et al. Correspondence of AQP4 expression and hypoxic-ischaemic brain oedema monitored by magnetic resonance imaging in the immature and juvenile rat. Eur J Neurosci. 2004;19(8):2261–9. Taniguchi M et al. Induction of aquaporin-4 water channel mRNA after focal cerebral ischemia in rat. Brain Res Mol Brain Res. 2000;78(1–2):131–7. Ke C et al. Impact of experimental acute hyponatremia on severe traumatic brain injury in rats: influences on injuries, permeability of blood–brain barrier, ultrastructural features, and aquaporin-4 expression. Exp Neurol. 2002;178(2):194–206. Saadoun S et al. Greatly improved neurological outcome after spinal cord compression injury in AQP4-deficient mice. Brain. 2008;131(Pt 4):1087–98. Kimura A et al. Protective role of aquaporin-4 water channels after contusion spinal cord injury. Ann Neurol. 2010;67(6):794–801. Zhao J et al. Sulforaphane enhances aquaporin-4 expression and decreases cerebral edema following traumatic brain injury. J Neurosci Res. 2005;82(4):499–506. Guo Q et al. Progesterone administration modulates AQP4 expression and edema after traumatic brain injury in male rats. Exp Neurol. 2006;198(2):469–78. Badaut J et al. Brain water mobility decreases after astrocytic aquaporin-4 inhibition using RNA interference. J Cereb Blood Flow Metab. 2011;31(3):819–31. Shlosberg D, Benifla M, Kaufer D, Friedman A. Blood-brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat Rev Neurol. 2010 6(7):393–403. Epub 2010 Jun 15. Beaumont A et al. Bolus tracer delivery measured by MRI confirms edema without blood–brain barrier permeability in diffuse traumatic brain injury. Act Neur S. 2006;96:171–4. Strbian D et al. The blood–brain barrier is continuously open for several weeks following transient focal cerebral ischemia. Neuroscience. 2008;153(1):175–81. Nag S, Venugopalan R, Stewart DJ. Increased caveolin-1 expression precedes decreased expression of occludin and claudin-5 during blood–brain barrier breakdown. Acta Neuropathol. 2007;114(5):459–69. Jiao H et al. Specific role of tight junction proteins claudin-5, occludin, and ZO-1 of the blood–brain barrier in a focal cerebral ischemic insult. J Mol Neurosci. 2011;44(2):130–9. Abdul Muneer PM. Inhibitory effects of alcohol on glucose transport across the blood–brain barrier leads to neurodegeneration: preventive role of acetyl-L: -carnitine. Psychopharmacology (Berl). 2011;214(3):707–18. Lin JL et al. Ascorbic acid prevents blood–brain barrier disruption and sensory deficit caused by sustained compression of primary somatosensory cortex. J Cereb Blood Flow Metab. 2010;30(6):1121–36. Liao CW et al. Blood–brain barrier impairment with enhanced SP, NK-1R, GFAP and claudin-5 expressions in experimental cerebral toxocariasis. Parasite Immunol. 2008;30(10):525–34. Pierre K, Pellerin L. Monocarboxylate transporters in the central nervous system: distribution, regulation and function. J Neurochem. 2005;94(1):1–14. Prins ML, Giza CC. Induction of monocarboxylate transporter 2 expression and ketone transport following traumatic brain injury in juvenile and adult rats. Dev Neurosci. 2006;28(4–5):447–56. Appelberg KS, Hovda DA, Prins ML. The effects of a ketogenic diet on behavioral outcome after controlled cortical impact injury in the juvenile and adult rat. J Neurotraum. 2009;26(4):497–506. Deane R, Wu Z, Zlokovic BV. RAGE (yin) versus LRP (yang) balance regulates alzheimer amyloid beta-peptide clearance through transport across the blood–brain barrier. Stroke. 2004;35(11 Suppl 1):2628–31. Miller DS. Regulation of P-glycoprotein and other ABC drug transporters at the blood–brain barrier. Trends Pharmacol Sci. 2010;31(6):246–54. Zlokovic BV et al. Low-density lipoprotein receptor-related protein-1: a serial clearance homeostatic mechanism controlling Alzheimer’s amyloid beta-peptide elimination from the brain. J Neurochem. 2010;115(5):1077–89. Pop, V., et al. Long-term alterations in the blood–brain barrier, cognitive impairment, and development of Alzheimer-type neuropathology after juvenile traumatic brain injury. XXVth International Symposium on Cerebral Blood Flow and Metabolism, Barcelona, Spain, JCBFM; 2011. Wu B et al. Age-related changes in P-glycoprotein expression in senescence-accelerated mouse. Curr Aging Sci. 2009;2(3):187–92. Wu B et al. RAGE, LDL receptor, and LRP1 expression in the brains of SAMP8. Neurosci Lett. 2009;461(2):100–5. Cirrito JR et al. P-glycoprotein deficiency at the blood–brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model. J Clin Invest. 2005;115(11):3285–90. Mawuenyega KG et al. Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science. 2010;330(6012):1774. Magnoni S, Brody DL. New perspectives on amyloid-beta dynamics after acute brain injury: moving between experimental approaches and studies in the human brain. Arch Neurol. 2010;67(9):1068–73. Abrahamson EE et al. Caspase inhibition therapy abolishes brain trauma-induced increases in Abeta peptide: implications for clinical outcome. Exp Neurol. 2006;197(2):437–50. Tran HT et al. Distinct temporal and anatomical distributions of amyloid-beta and tau abnormalities following controlled cortical impact in transgenic mice. PLoS One. 2011;6(9):e25475. Tran HT et al. Controlled cortical impact traumatic brain injury in 3xTg-AD mice causes acute intra-axonal amyloid-beta accumulation and independently accelerates the development of tau abnormalities. J Neurosci. 2011;31(26):9513–25. Uryu K et al. Repetitive mild brain trauma accelerates Abeta deposition, lipid peroxidation, and cognitive impairment in a transgenic mouse model of Alzheimer amyloidosis. J Neurosci. 2002;22(2):446–54. Nakagawa Y et al. Traumatic brain injury in young, amyloid-beta peptide overexpressing transgenic mice induces marked ipsilateral hippocampal atrophy and diminished Abeta deposition during aging. J Comp Neurol. 1999;411(3):390–8. Nakagawa Y et al. Brain trauma in aged transgenic mice induces regression of established abeta deposits. Exp Neurol. 2000;163(1):244–52. Loane DJ et al. Modulation of ABCA1 by an LXR agonist reduces beta-amyloid levels and improves outcome after traumatic brain injury. J Neurotraum. 2011;28(2):225–36. Del Valle J et al. Cerebral amyloid angiopathy, blood–brain barrier disruption and amyloid accumulation in SAMP8 mice. Neurodegener Dis. 2011;8(6):421–9. Hardy J. The amyloid hypothesis for Alzheimer’s disease: a critical reappraisal. J Neurochem. 2009;110(4):1129–34. Canepa E et al. Cholesterol and amyloid-beta: evidence for a cross-talk between astrocytes and neuronal cells. J Alzheimers Dis. 2011;25(4):645–53. Butterfield DA et al. Elevated oxidative stress in models of normal brain aging and Alzheimer’s disease. Life Sci. 1999;65(18–19):1883–92. Markesbery WR, Lovell MA. Damage to lipids, proteins, DNA, and RNA in mild cognitive impairment. Arch Neurol. 2007;64(7):954–6. Lovell MA, Markesbery WR. Oxidative damage in mild cognitive impairment and early Alzheimer’s disease. J Neurosci Res. 2007;85(14):3036–40. Lovell MA, Markesbery WR. Oxidative DNA damage in mild cognitive impairment and late-stage Alzheimer’s disease. Nucleic Acids Res. 2007;35(22):7497–504. Shao C et al. Oxidative stress in head trauma in aging. Free Radic Biol Med. 2006;41(1):77–85. Berchtold NC et al. Gene expression changes in the course of normal brain aging are sexually dimorphic. Proc Natl Acad Sci USA. 2008;105(40):15605–10. Uryu K et al. Age-dependent synuclein pathology following traumatic brain injury in mice. Exp Neurol. 2003;184(1):214–24. Uryu K et al. Multiple proteins implicated in neurodegenerative diseases accumulate in axons after brain trauma in humans. Exp Neurol. 2007;208(2):185–92. Nicolakakis N, Hamel E. Neurovascular function in Alzheimer’s disease patients and experimental models. J Cereb Blood Flow Metab. 2011;31(6):1354–70.