By Ramon Diaz-Arrastia, MD, PhD
Traumatic brain injury (TBI) has been one of the most common maladies in human history.1 Recent quantitative studies from burial sites of prehistoric modern humans2;3 indicate that approximately one-third of our ancestors experienced cranial trauma sufficient to result in a skull fracture. This high rate of TBI in prehistoric humans makes it likely that genetic variants that confer resistance to brain trauma, or foster repair and plasticity of injured neural tissue, would have been selectively favored through evolution. TBI remains a major problem in modern societies, primarily as a consequence of traffic accidents and falls. In the United States alone, an estimated 1.7 million people sustain a TBI annually, of which 275,000 require hospitalization and 52,000 die.4 Rates are even higher in developing countries.5
TBI is perhaps the best established environmental risk factor for dementia. Cross-sectional and longitudinal studies over the past two decades indicate that the odds ratio (OR) for late life dementia is from 1.5 – 4.0 in those who have sustained a TBI in early or mid-life. As expected, injury severity has an effect. For those who sustained a severe TBI, the risk is approximately 4-fold; after a moderate TBI the risk is only about 2-fold; and even after a mild TBI risks of 1.3 – 1.8 fold have been reported in recent large epidemiologic studies. Available data allow a rough calculation of how much of the population’s burden of dementia is attributable to TBI. Assuming that the cumulative lifetime incidence of TBI requiring hospitalization is 10%, a reasonable estimate based on the most recent data, the attributable risk of dementia to TBI is in the range of 5 – 15%.6
Little information can be gleaned from the epidemiologic studies regarding specific clinical and pathologic features of dementia associated with TBI. Most studies have focused on Alzheimer’s disease (AD), and in the better studies7-9 the diagnosis of probable or possible AD was made using established NINDS-ADRDA criteria.10 However, pathologic confirmation of AD diagnosis, which remains the gold standard for diagnosis, is not available in these epidemiologic studies. Studies which have analyzed the clinical features of dementia in TBI survivors indicates that neuropsychiatric symptoms such as depression, anxiety, irritability, are more common in TBI-associated dementia than in typical AD.11
Whereas the long-term consequences of a single episode of primarily moderate-to-severe TBI have only recently been recognized, it has long been known that multiple mild TBIs result in late-life dementia. Recent studies of retired professional athletes who had sustained multiple concussions and developed dementia reported prominent tau-immunoreactive neurofibrillary and astrocytic tangles, but amyloid- β pathology was noted in less than half the cases. The distribution of neurofibrillary tangles differs from that seen in AD and represents a distinct pathology, termed chronic traumatic encephalopathy (CTE).12 It is unknown whether similar findings are noted in individuals who sustained a single moderate or severe TBI, a population several orders of magnitude larger than that of retired professional athletes.
In summary, TBI is common in modern societies, and advanced neurosurgical and neurological care allows most victims of even severe injuries to survive for many decades, albeit sometimes with disabilities. One of the most feared consequences of TBI is dementia. Epidemiologic studies indicate that TBI in early to mid-life is associated with an increased risk of dementia in late life, in the range of two- to four- fold compared to the general population. This risk appears to be much higher in the setting of multiple TBIs, although research is this area is in its infancy. Understanding the features of dementia after TBI is critically important to society. While currently there are no effective therapies available to treat or prevent AD, several such therapies are in the horizon.13 If TBI survivors are at increased risk of AD-type neurodegeneration, early recognition will be essential in order to implement preventive therapies. Alternatively, if TBI survivors experience dementia as a result of an alternate pathologic process, such as CTE, identifying early and pre-clinical diagnostic biomarkers is an essential first step for developing effective therapies. Finally, the recognition that certain members of society, such as military service members and professional athletes, are at particular risk of TBI-related dementia should stimulate research on preventative strategies focused on these individuals.
Dr. Diaz-Arrastia is Professor of Neurology, Uniformed Services University of the Health Sciences, and Director of Clinical Research at the Center for Neuroscience and Regenerative Medicine (CNRM). Dr. Diaz-Arrastia’s research interests are focused in the area of understanding the molecular, cellular, and tissue level mechanisms of secondary neuronal injury and neuroregeneration. Dr. Diaz-Arrastia has published over 125 peer-reviewed primary research papers, as well as over 20 invited reviews and book chapters. He has also served in several national committees related to TBI research and practice. He has served on expert panels convened by the Institute of Medicine, the National Institute of Neurological Disorders and Stroke, the National Institute of Aging, and the Department of Defense. He is also a peer reviewer for the leading journals in neurology, neuroscience, neurotrauma, and neurorehabilitation.
(1) Finger S. Origins of Neuroscience: A History of Explorations into Brain Function. New York: Oxford University Press, 1994.
(2) Tung TA. Trauma and violence in the Wari empire of the Peruvian Andes: warfare, raids, and ritual fights. Am J Phys Anthropol 2007;133:941-956.
(3) Torres-Rouff C, Costa Junqueira MA. Interpersonal violence in prehistoric San Pedro de Atacama, Chile: behavioral implications of environmental stress. Am J Phys Anthropol 2006;130:60-70.
(4) Faul M, Xu L, Wald MW, Coronado VG. Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations, and Deaths 2002 – 2006. Atlanta (GA): Centers for Disease Control and Prevention, National Center for Injury Prevention and Control, 2010.
(5) Thurman DJ, Coronado V, Selassie A. The Epidemiology of TBI: Implications for Public Health. In: Zasler ND, Katz DI, Zafonte RD, eds. Brain Injury Medicine: Principles and Practice. New York, NY: Demos; 2007;45-55.
(6) Kahn HA, Sempos CT. Attributable Risk. Statistical Methods in Epidemiology. New York: Oxford University Press; 1989;72-84.
(7) 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 Psychiat 2003;74:857-862.
(8) Guo Z, Cupples LA, Kurz A et al. Head injury and risk of AD in the MIRAGe study. Neurology 2000;54:1316-1323.
(9) Plassman BL, Havlik RJ, Steffens DC et al. Documented head injury in early adulthood and risk of Alzheimer’s disease and other dementias. Neurology 2000;55:1158-1166.
(10) McKhann G, Drachman D, Folstein M et al. Clinical diagnosis of Alzheimer’s disease: Report of the NINDS-ADRDA work group under the auspices of the Department of Health and Human Services Task Force of Alzheimer’s disease. Neurology 1984;34:939-944.
(11) Sayed N, Culver C, Dams-O’Connor K, Hammond F, Diaz-Arrastia R. Clinical phenotype of dementia after traumatic brain injury. J Neurotrauma 2013;30:1117-1122.
(12) McKee AC, Cantu RC, Nowinski CJ et al. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol 2009;68:709-735.
(13) Savonenko AV, Melnikova T, Hiatt A et al. Alzheimer’s therapeutics: translation of preclinical science to clinical drug development. Neuropsychopharmacology 2012;37:261-277.