Traumatic brain injury (TBI) has become a hot topic. Between the high number of military personnel exposed to blasts from homemade bombs and a new awareness of the seriousness of concussive sports injuries, the disorder has grabbed the attention of many researchers. One especially troubling question is whether brain injury seeds the development of dementia. The data to date are suggestive, but far from conclusive.
An important factor to keep in mind is the nature of the brain trauma. “We should not assume that the processes occurring after a single severe injury are identical to those occurring after repetitive concussive injuries,” said David Brody of Washington University in St. Louis, Missouri. Brody is currently comparing mouse models of each type of head trauma, and said that preliminary data suggest there are substantial differences between the two, although it is too early to give details. One feature shared in common is axonal injury—these long, thin nerve fiber tracts appear to be supremely vulnerable to shearing, stretching, and twisting damage (see Smith et al., 2003). Yet even for axons, Brody said, the exact nature of the injury may differ in severe versus mild TBI.
Aβ deposits (red) and APP (green) at a site of axonal injury in mouse brain. Image credit: David Brody and Hien Tran
Severe TBI has been better studied, with a more extensive literature. “Most of the evidence for increased risk of dementia of the Alzheimer’s type is after single severe injuries,” Brody points out (see, e.g., Mortimer et al., 1991; Jellinger et al., 2001; Jellinger et al., 2001; and Fleminger et al., 2003). In one study of almost 2,000 World War II veterans, those with moderate to severe head injuries had twice the risk of developing dementia, and for those with an ApoE4 allele, the risk seemed to increase further (see Plassman et al., 2000).
Numerous papers agree that ApoE4 increases TBI-related dementia risk (see, e.g., Isoniemi et al., 2006; Mauri et al., 2006; and Luukinen et al., 2008), with one influential study finding that people with head injuries had a 10-fold increase in AD risk if they also carried an ApoE4 allele (see Mayeux et al., 1995). The finding is not universal, with a few small or short-term studies showing no association (see, e.g., Chamelian et al., 2004 and Han et al., 2007). Overall, however, the data imply a role for AD-related processes after head injury.
Does the increased risk for AD mean that severe brain injury triggers Alzheimer’s pathology? Not necessarily, Brody said. Such injuries might merely lower a person’s overall brain health and cognitive reserve, leading to an earlier onset of AD symptoms later in life. Or some third factor could be at work. For example, a recent review posited that sleep apnea, which is common among TBI patients, may be a source of cognitive impairment and dementia risk after brain injury (see O’Hara et al., 2009). This idea would be encouraging, since sleep apnea is treatable.
Several studies do point to a possible link between severe brain injury and Alzheimer’s disease processes, however. In animal models, amyloid precursor protein (APP) accumulates in injured axons, where it may be snipped by β-secretase, presenilin-1, or caspase-3 to make Aβ (see Stone et al., 2002 and Chen et al., 2004). Inhibiting caspase-3 lowers Aβ levels after brain injury and improves recovery in mice (see Abrahamson et al., 2006). Likewise, administration of anti-APP antibody to rats with rattled brains reduces neuron and glia death and improves cognitive function (see Itoh et al., 2009 and Itoh et al., 2009). In a mouse study, inhibition of APP-cleaving β- and γ-secretases had similar beneficial effects (see ARF related news story on Loane et al., 2009). These findings suggest a role for amyloid pathology in the deficits caused by head injury, at least in animal models.
In humans, researchers have seen contradictory changes in the levels of Aβ40 and Aβ42 in cerebrospinal fluid after severe brain injury, with some studies showing an increase and some a decrease (see Emmerling et al., 2000; Franz et al., 2003; and Olsson et al., 2004). The literature on amyloid changes in the brain is also confusing. In about one-third of brain samples surgically removed within hours of severe TBI, researchers have found diffuse Aβ plaques (see Ikonomovic et al., 2004). TBI brains containing plaques also show higher levels of soluble Aβ42 (see DeKosky et al., 2007). Brody and collaborators measured levels of extracellular Aβ in brain interstitial fluid taken from drainage catheters of trauma patients in intensive care, however, and found peptide levels were lower after the brain injury, when the injured brain’s activity was low, and gradually rose as the brain recovered and resumed activity (see ARF related news story on Brody et al., 2008; Schwetye et al., 2010; and reviewed in Magnoni and Brody, 2010).
“It is possible that in humans with TBI, extracellular amyloid-β levels are reduced in the soluble form, yet intracellular amyloid-β levels are increased in an insoluble form,” Brody said, emphasizing that the brain contains different pools of Aβ. “That would fit with all the available animal and human literature.” He notes there is no data as yet on the oligomerization status of the soluble Aβ, a key factor for determining its toxicity.
Despite the research to date, it is not clear how injury-associated amyloid release relates to AD. Do diffuse post-injury deposits go on to seed Alzheimer’s-like plaques? At least one study that examined TBI patients surviving up to three years after injury suggests not, finding that, despite the presence of large amounts of APP and Aβ, there were “virtually no” Aβ plaques in these brains (see Chen et al., 2008). This would suggest that post-injury deposits may be a fleeting phenomenon that the brain subsequently clears. Likewise, at autopsy, only about one-third of people who have had severe brain trauma show amyloid deposits, Brody said.
Mark Burns, at Georgetown University in Washington, DC, wrote to ARF, “This leads to a very confusing picture of why the brain becomes susceptible to AD after TBI. I suspect the answer may be that the brain has suffered a severe stress that leaves it primed and vulnerable to other stressors as time progresses.” This might lead to an earlier onset of AD, Burns suggested.
However, Sam Gandy at Mount Sinai Medical Center in New York City told ARF that he is convinced by the data that Aβ42 accumulation triggered by brain injury does play a role in susceptibility to AD. Cognitive reserve may be lost as well, Gandy wrote, both through amyloid-related and non-amyloid pathways.
Brody points to the need for more standardized, validated animal models of brain injury to sort all this out. Such models are in development (see, e.g., Brody et al., 2007), but much more work will be needed to answer these questions. To find out what role tau plays in chronically concussed brains, see Part 3.—Madolyn Bowman Rogers.
- Targeting Secretases Reduces Effects of Head Injury
- Soluble Aβ—Bane or Boon? Real-time Data in Humans Yield New Insight
- Stress and Trauma: Shaken Brains, Shaken Lives
- Stress and Trauma: New Frontier Lures Alzheimer’s Researchers
- Stress and Trauma: Blast Injuries in the Military
- Stress and Trauma: The Puzzle of Post-traumatic Stress Disorder
- Stress and Trauma: Tackling Post-traumatic Stress Disorder
- Smith DH, Meaney DF, Shull WH. .
- Mortimer JA, van Duijn CM, Chandra V, Fratiglioni L, Graves AB, Heyman A, Jorm AF, Kokmen E, Kondo K, Rocca WA. Head trauma as a risk factor for Alzheimer's disease: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group. Int J Epidemiol. 1991;20 Suppl 2:S28-35. PubMed.
- Jellinger KA, Paulus W, Wrocklage C, Litvan I. Effects of closed traumatic brain injury and genetic factors on the development of Alzheimer's disease. Eur J Neurol. 2001 Nov;8(6):707-10. PubMed.
- Jellinger KA, Paulus W, Wrocklage C, Litvan I. Traumatic brain injury as a risk factor for Alzheimer disease. Comparison of two retrospective autopsy cohorts with evaluation of ApoE genotype. BMC Neurol. 2001 Dec 18;1:3. PubMed.
- Fleminger S, Oliver DL, Lovestone S, Rabe-Hesketh S, Giora A. Head injury as a risk factor for Alzheimer's disease: the evidence 10 years on; a partial replication. J Neurol Neurosurg Psychiatry. 2003 Jul;74(7):857-62. PubMed.
- Plassman BL, Havlik RJ, Steffens DC, Helms MJ, Newman TN, Drosdick D, Phillips C, Gau BA, Welsh-Bohmer KA, Burke JR, Guralnik JM, Breitner JC. Documented head injury in early adulthood and risk of Alzheimer's disease and other dementias. Neurology. 2000 Oct 24;55(8):1158-66. PubMed.
- Isoniemi H, Tenovuo O, Portin R, Himanen L, Kairisto V. Outcome of traumatic brain injury after three decades--relationship to ApoE genotype. J Neurotrauma. 2006 Nov;23(11):1600-8. PubMed.
- Mauri M, Sinforiani E, Bono G, Cittadella R, Quattrone A, Boller F, Nappi G. Interaction between Apolipoprotein epsilon 4 and traumatic brain injury in patients with Alzheimer's disease and Mild Cognitive Impairment. Funct Neurol. 2006 Oct-Dec;21(4):223-8. PubMed.
- Luukinen H, Jokelainen J, Kervinen K, Kesäniemi YA, Winqvist S, Hillbom M. Risk of dementia associated with the ApoE epsilon4 allele and falls causing head injury without explicit traumatic brain injury. Acta Neurol Scand. 2008 Sep;118(3):153-8. PubMed.
- Mayeux R, Ottman R, Maestre G, Ngai C, Tang MX, Ginsberg H, Chun M, Tycko B, Shelanski M. Synergistic effects of traumatic head injury and apolipoprotein-epsilon 4 in patients with Alzheimer's disease. Neurology. 1995 Mar;45(3 Pt 1):555-7. PubMed.
- Chamelian L, Reis M, Feinstein A. Six-month recovery from mild to moderate Traumatic Brain Injury: the role of APOE-epsilon4 allele. Brain. 2004 Dec;127(Pt 12):2621-8. PubMed.
- Han SD, Drake AI, Cessante LM, Jak AJ, Houston WS, Delis DC, Filoteo JV, Bondi MW. Apolipoprotein E and traumatic brain injury in a military population: evidence of a neuropsychological compensatory mechanism?. J Neurol Neurosurg Psychiatry. 2007 Oct;78(10):1103-8. PubMed.
- O'Hara R, Luzon A, Hubbard J, Zeitzer JM. Sleep apnea, apolipoprotein epsilon 4 allele, and TBI: mechanism for cognitive dysfunction and development of dementia. J Rehabil Res Dev. 2009;46(6):837-50. PubMed.
- Stone JR, Okonkwo DO, Singleton RH, Mutlu LK, Helm GA, Povlishock JT. Caspase-3-mediated cleavage of amyloid precursor protein and formation of amyloid Beta peptide in traumatic axonal injury. J Neurotrauma. 2002 May;19(5):601-14. PubMed.
- Chen XH, Siman R, Iwata A, Meaney DF, Trojanowski JQ, Smith DH. Long-term accumulation of amyloid-beta, beta-secretase, presenilin-1, and caspase-3 in damaged axons following brain trauma. Am J Pathol. 2004 Aug;165(2):357-71. PubMed.
- Abrahamson EE, Ikonomovic MD, Ciallella JR, Hope CE, Paljug WR, Isanski BA, Flood DG, Clark RS, Dekosky ST. Caspase inhibition therapy abolishes brain trauma-induced increases in Abeta peptide: implications for clinical outcome. Exp Neurol. 2006 Feb;197(2):437-50. PubMed.
- Itoh T, Satou T, Nishida S, Tsubaki M, Hashimoto S, Ito H. Expression of amyloid precursor protein after rat traumatic brain injury. Neurol Res. 2009 Feb;31(1):103-9. PubMed.
- Itoh T, Satou T, Nishida S, Tsubaki M, Hashimoto S, Ito H. Improvement of cerebral function by anti-amyloid precursor protein antibody infusion after traumatic brain injury in rats. Mol Cell Biochem. 2009 Apr;324(1-2):191-9. PubMed.
- Loane DJ, Pocivavsek A, Moussa CE, Thompson R, Matsuoka Y, Faden AI, Rebeck GW, Burns MP. Amyloid precursor protein secretases as therapeutic targets for traumatic brain injury. Nat Med. 2009 Apr;15(4):377-9. PubMed.
- Emmerling MR, Morganti-Kossmann MC, Kossmann T, Stahel PF, Watson MD, Evans LM, Mehta PD, Spiegel K, Kuo YM, Roher AE, Raby CA. Traumatic brain injury elevates the Alzheimer's amyloid peptide A beta 42 in human CSF. A possible role for nerve cell injury. Ann N Y Acad Sci. 2000 Apr;903:118-22. PubMed.
- Franz G, Beer R, Kampfl A, Engelhardt K, Schmutzhard E, Ulmer H, Deisenhammer F. Amyloid beta 1-42 and tau in cerebrospinal fluid after severe traumatic brain injury. Neurology. 2003 May 13;60(9):1457-61. PubMed.
- Olsson A, Csajbok L, Ost M, Höglund K, Nylén K, Rosengren L, Nellgård B, Blennow K. Marked increase of beta-amyloid(1-42) and amyloid precursor protein in ventricular cerebrospinal fluid after severe traumatic brain injury. J Neurol. 2004 Jul;251(7):870-6. PubMed.
- Ikonomovic MD, Uryu K, Abrahamson EE, Ciallella JR, Trojanowski JQ, Lee VM, Clark RS, Marion DW, Wisniewski SR, Dekosky ST. Alzheimer's pathology in human temporal cortex surgically excised after severe brain injury. Exp Neurol. 2004 Nov;190(1):192-203. PubMed.
- Dekosky ST, Abrahamson EE, Ciallella JR, Paljug WR, Wisniewski SR, Clark RS, Ikonomovic MD. Association of increased cortical soluble abeta42 levels with diffuse plaques after severe brain injury in humans. Arch Neurol. 2007 Apr;64(4):541-4. PubMed.
- Brody DL, Magnoni S, Schwetye KE, Spinner ML, Esparza TJ, Stocchetti N, Zipfel GJ, Holtzman DM. Amyloid-beta dynamics correlate with neurological status in the injured human brain. Science. 2008 Aug 29;321(5893):1221-4. PubMed.
- Schwetye KE, Cirrito JR, Esparza TJ, Mac Donald CL, Holtzman DM, Brody DL. Traumatic brain injury reduces soluble extracellular amyloid-β in mice: a methodologically novel combined microdialysis-controlled cortical impact study. Neurobiol Dis. 2010 Dec;40(3):555-64. PubMed.
- 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 Sep;67(9):1068-73. PubMed.
- Chen XH, Johnson VE, Uryu K, Trojanowski JQ, Smith DH. A lack of amyloid beta plaques despite persistent accumulation of amyloid beta in axons of long-term survivors of traumatic brain injury. Brain Pathol. 2009 Apr;19(2):214-23. PubMed.
- Brody DL, Mac Donald C, Kessens CC, Yuede C, Parsadanian M, Spinner M, Kim E, Schwetye KE, Holtzman DM, Bayly PV. .