Mild Traumatic Brain Injury & Risk for Alzheimer’s Disease

By: 

Grant L. Iverson, PhD

This article is derived, in large part, from the following book chapter and review paper: Iverson, G. L., Lange, R. T., Gaetz, M., & Zasler, N. D.  (2006). MTBI. In N. D. Zasler, D. I. Katz, & R. D. Zafonte (Eds.), Brain injury medicine: Principles and practice. New York: Demos Medical Publishing; Iverson, G. L. (2005). Outcome from Mild Traumatic Brain Injury. Current Opinion in Psychiatry, 18, 301-317.

A provocative, confusing, and controversial issue relating to outcome from mild traumatic brain injury (MTBI) is whether this injury increases a person’s risk for the future development of Alzheimer’s disease. This article provides a review of literature pertaining to this issue. The article is divided into the following four sections: (1) risk factors for Alzheimer’s disease, (2) mild traumatic brain injury: definition & pathophysiology, (3) risk for Alzheimer’s disease following MTBI, and (4) conclusions.

Risk Factors for Alzheimer’s Disease

Alzheimer’s disease, the most common form of dementia, is a progressive and devastating brain disease. It results in a progressive deterioration of neurocognitive (such as learning, memory, higher-order language skills, judgment, and reasoning) and functional abilities. As the disease progresses, some patients experience pronounced personality and behavior changes including anxiety, agitation, suspiciousness, delusions, and hallucinations. The disease can be frightening and overwhelming for patients and their families.

The greatest risk factor for developing Alzheimer’s disease is age. Meta-analytic studies have consistently found that the prevalence of the disease around the world increases with age (e.g., 1-4). In an early meta-analysis of 22 studies, Jorm and colleagues (2) reported that the prevalence of Alzheimer’s disease doubled every 4.5 years; they reported the following prevalence rates stratified by age group: 65-69 years (1.4%), 70-74 years (2.8%), 75-79 years (5.6%), 80-84 years (11.1%), and 85 years or more (23.6%). The risk for developing the disease is low in a person’s 60’s and high after the age of 85 (perhaps 25-50% of older adults).

Not surprisingly, there has been considerable interest in genetics [particularly the apolipoprotein E (ApoE) gene (5-8)], singly or in combination, with lifestyle as a risk factor for the disease. Genetics clearly represent a risk factor. Another predominant risk factor appears to be cardiovascular and cerebrovascular health and disease, broadly defined. There is ongoing interest in cerebrovascular disease and vascular risk factors (9, 10); cardiovascular disease and subgroups of patients with peripherial arterial disease (11); high cholesterol (12); and elevated plasma total homocysteine concentrations and low serum folate concentrations (13). The risk for Alzheimer’s disease appears to increase with the number of vascular risk factors (diabetes + hypertension + heart disease + current smoking), with diabetes and current smoking being the strongest risk factors in isolation or in combination in a recent study (14).

The search for risk factors is diverse and ongoing, and includes a variety of cellular processes such as oxidative stress, disturbed protein metabolism, and their interaction (15, 16); zinc metabolism (17); loss of microglial cell function (18); and decreased melatonin (19). Environmental factors, such as heavy metal exposure (20), have been investigated for many years.

Nutrition and lifestyle factors, such as midlife obesity (21), lack of exercise (22), and watching too much television in middle-adulthood (presumably as a marker for reduced participation in intellectually stimulating activities; 23), have been associated with an increased risk for Alzheimer’s disease. Even a man’s height has been associated with risk. Researchers have reported that short men are at increased risk (presumably due to its association with childhood nutrition and other risk factors for dementia; 24).

Mental health problems, such as a history of depression in adulthood (25), have been associated with an increased risk for the disease. Researchers have reported that this risk appears to be greater for men (26). As seen in this brief overview of the risk factor literature, there many factors that have been linked statistically to the disease. Much research is needed to examine combinations of these factors and their combined relative and absolute risk for developing the disease. Researchers and clinicians interested in risk for Alzheimer’s disease in patients who have sustained traumatic brain injuries, especially mild traumatic brain injuries, should consider this possible risk factor in the context of multiple other more important risk factors such as age, genetics, and vascular disease.

Mild Traumatic Brain Injury: Definition & Epidemiology

In 2004, a comprehensive review of the literature on mild traumatic brain injury (MTBI) was published in a series of articles in the Journal of Rehabilitation Medicine (e.g., 27-31). The World Health Organization (WHO) Collaborating Centre Task Force on Mild Traumatic Brain Injury provided the definition reprinted below.

“MTBI is an acute brain injury resulting from mechanical energy to the head from external physical forces. Operational criteria for clinical identification include: (i) 1 or more of the following: confusion or disorientation, loss of consciousness for 30 minutes or less, post-traumatic amnesia for less than 24 hours, and/or other transient neurological abnormalities such as focal signs, seizure, and intracranial lesion not requiring surgery; and/or? (ii) Glasgow Coma Scale score of 13–15 after 30 minutes post-injury or later upon presentation for healthcare.

These manifestations of MTBI must not be due to drugs, alcohol, medications, caused by other injuries or treatment for other injuries (e.g. systemic injuries, facial injuries or intubation), caused by other problems (e.g. psychological trauma, language barrier or coexisting medical conditions) or caused by penetrating craniocerebral injury” (page 115; 32)

This definition is consistent with the widely cited definition developed by the Mild Traumatic Brain Injury Committee of the Head Injury Interdisciplinary Special Interest Group of the American Congress of Rehabilitation Medicine (33). It is also consistent with the Center for Disease Control (CDC) working group definition set out in a report to the United States Congress in 2003 (34), and the definitions used by many researchers over the past 20 years.

The potential for incomplete recovery and poor psychosocial outcome following mild traumatic brain injury (MTBI) has been recognized as a public health problem (35-37). Unfortunately, these injuries are common in daily life and in sports. Concussions in sports, for example, are very common. In a recent study, 30% of high school football players reported at least one previous concussion; 15% reported that they experienced a concussion during the current football season (38). Sosin et al. (39), based on the National Health Interview Survey in 1991, estimated that 1.5 million Americans suffer a traumatic brain injury each year (i.e., 618/100,000). The vast majority of these injuries are mild in severity. The prevalence estimate of Sosin and colleagues is much higher than previous estimates based on hospital admissions because most people who sustain an MTBI are not evaluated in the emergency department or admitted to the hospital (39). Bazarian and colleagues (40) reported that 56/100,000 people are evaluated in the emergency department each year for anisolated MTBI. Of course, many other patients sustain MTBIs as one of several injuries (e.g., orthopedic injuries following a motor vehicle accident).

Pathophysiology

It is necessary to review the pathophysiology of MTBI in order to properly consider the possible relation between this injury and the future development of Alzheimer’s disease. It is important to note that the pathophysiology of MTBI appears to be predominately neurometabolic and reversible. However, some people with this injury have macroscopic structural damage visible with static neuroimaging (e.g., CT or MRI; 30, 41-46) and permanent cellular damage that is not visible through neuroimaging (47). Without question, the pathophysiology and pathoanatomy of MTBI falls on a broad spectrum. MTBIs are not created equally and it is a mistake to adopt a simplistic binary approach to conceptualizing this injury (e.g., present or absent). The spectrum of pathophysiology is illustrated in Figure 1.

Figure 1. Spectrum of MTBI pathophysiology.
 
Very mild, rapidly reversible neurometabolic dysfunction Prolonged, multilayered, neurometabolic cascade with possible minor long-lasting cellular dysfunction Macroscopic abnormality (contusion), localized and more widespread cellular damage and dysfunction

A book chapter by Giza and Hovda (48) provides an excellent summary of the pathophysiology of concussion, learned mostly from animal studies. I have relied on this chapter to summarize the complex interwoven cellular and vascular changes that occur following a concussion. This has been conceptualized as a multilayered neurometabolic cascade whereby affected cells typically recover, although under certain circumstances they might degenerate and die. The primary mechanisms include ionic shifts, abnormal energy metabolism, diminished cerebral blood flow, and impaired neurotransmission.

Immediately after a concussive injury, there is an indiscriminate release of neurotransmitters and uncontrolled ionic fluxes. Potassium (K+) rapidly leaves the cell. Shortly after injury, and for a prolonged period of time, there is an influx of calcium (Ca2+). When the ionic gradients are disrupted, cells respond by activating ion pumps in an attempt to restore the normal membrane potential. Because these pumps require energy to function, more glucose is utilized. This leads to dramatic increases in the local cerebral metabolic rate for glucose. This hypermetabolism occurs in the context of decreased cerebral blood flow , which can contribute to a disparity between glucose supply and demand. In addition to increased glucose utilization, there may be impaired oxidative metabolism and diminished mitochondrial function. As a result, anaerobic (not requiring oxygen) energy pathways may be over-utilized. Elevated lactate can occur as a by-product of anaerobic energy production (and through other mechanisms). In addition, intracellular magnesium levels decrease significantly and remain depressed for several days following injury. This is important because magnesium is essential for generation of adenosine-triphosphate (ATP - energy production). Magnesium is also essential for the initiation of protein synthesis and the maintenance of the cellular membrane potential .

The sustained influx of Ca2+ has at least two important effects: (1) mitochondrial accumulations of Ca2+, and (2) initiation of a pathophysiologic process of axonal injury. The increased mitochondrial Ca2+ can lead to metabolic dysfunction and eventually energy failure. Abnormally high intracellular Ca2+ levels can initiate an irreversible process of destruction of microtubules within axons. Coupled with neurofilament damage that can occur with stretch injury, microtubule damage can impair axoplasmic flow along the length of the axon. When this occurs, axons can swell and separate.

When entire cells die following MTBI (NB: a small number), the mechanism of death relates to the spectrum of necrosis; however, researchers have reported that apoptosis (programmed cell death) appears to contribute to cell mortality in both grey and white matter following MTBI (51). Thus, the mechanisms of cell death might represent a continuum between apoptotic and necrotic pathways (52)It is important to note that cell death is closely related to injury severity. Very mild concussions likely produce virtually no permanent damage to cells resulting in long-term symptoms or problems whereas severe traumatic brain injuries, especially those involving considerable forces, often produce widespread cellular death and dysfunction with clear functional consequences.

Fortunately, the majority of the pathophysiology of concussion is neurometabolic and reversible. The brain undergoes dynamic restoration in the initial days and weeks post injury. That is why most people who sustain MTBIs appear to recover fully. Permanent cognitive, psychological, or psychosocial problems due to the biological effects of this injury are relatively uncommon in trauma patients and rare in athletes (see 27, 53-57 for recent comprehensive reviews). When considering the full spectrum of MTBIs, the prevalence of incomplete recovery likely is considerably lower than the widely-cited 15% estimate (for a discussion of this point, see 55, 58). Despite decades of research, slow or incomplete recovery from MTBI remains poorly understood. The spectrum of recovery from MTBI is illustrated in Figure 2.

Figure 2. Continuum of recovery from MTBI.
 
Rapid/Complete 
(Minutes/Hours)
Rapid/Complete
(Hours/Several Days)
Typical/Likely Complete
(1-12 Weeks)
Prolonged 
(3-6 Months)
Atypical/Slow
(6-12 Months)
Incomplete
Long-Lasting

Recovery is influenced by numerous and diverse biopsychosocial factors. It is a critical mistake to conceptualize recovery from a predominately pathophysiological perspective. The underlying cause for poor outcome in patients falling in the atypical or incomplete end of the spectrum is likely multifactorial in most cases. Poor outcome typically involves combinations of factors that are modestly-related, or even unrelated, to the original severity of injury. Some of these factors include pre-existing personality characteristics, life stress, psychiatric conditions, or substance abuse problems (59-61); co-morbid conditions, such as chronic pain, depression, post-traumatic stress disorder, life stress, or substance abuse (62-68); litigation (69-71); exaggeration or malingering (72-76); and symptom expectations, misattribution, and response bias (67, 77-83). A biopsychosocial perspective is the only reasonable approach for conceptualizing poor long-term outcome following MTBI.

A controversial and poorly understood issue relating to outcome from MTBI is whether this injury increases a person’s risk for the future development of Alzheimer’s disease. A brief review of the literature on risk for the disease in people who have sustained traumatic brain injuries, of all severities, is provided below.

Risk for Alzheimer’s Disease Following MTBI

There has been considerable research interest regarding whether mild, repetitive mild, moderate, or severe traumatic brain injuries increase a person’s risk for developing Alzheimer’s disease. This research has been ongoing, with mixed results, for more than 20 years. At this point in time, there is no clear consensus in the literature.

A prima facie plausible theory is that severe traumatic brain injuries reduce “cognitive reserve,” resulting in increased vulnerability to developing the disease (84). The animal literature has revealed evidence that some of the neuropathological features of Alzheimer’s disease arise shortly after traumatic brain injury (see 85, 86 for reviews), and human autopsy studies also have supported these findings (87, 88). If a severe traumatic brain injury results in widespread cellular death, it seems reasonable to assume that the injured person would be more vulnerable to the adverse neurocognitive effects of natural aging and degenerative brain disease.

The relation between traumatic brain injury and risk for Alzheimer’s disease is very difficult to study, from a methodological perspective. One methodology is to examine a large, cross-sectional cohort of subjects with history of brain injury identified retrospectively and dementia diagnosed in the present. Another methodology is to attempt to follow patients prospectively. Over the years, using varying research designs and methodologies (including autopsy studies), some researchers have reported a statistical relation between a history of traumatic brain injury (mostly moderate or severe) and a current diagnosis of Alzheimer’s disease (e.g., 89-102). However, other researchers have frequently failed to find this association (e.g., 103-111).

There has been considerable interest in whether genetic factors influence the susceptibility of the human brain to injury and/or the capacity for recovery. If so, these genetic factors could influence the relation between traumatic brain injury and the development of Alzheimer’s disease. Researchers have been most interested in the ApoE allele; ApoE4 reportedly is associated with worse outcome following traumatic brain injury (e.g., see 112, 113 for reviews) whereas ApoE3 might be neuroprotective. Thus, genetics might play an important role in the degree of permanent brain damage sustained following traumatic injury.

The logical extension is to study whether genetics, in combination with traumatic brain injury (typically moderate or severe TBI), increase one’s risk for Alzheimer’s disease. Researchers have reported mixed and contradictory findings in this area. Some researchers have reported a positive association between TBI, ApoE, and dementia (e.g., 114, 115), while other researchers have not found this relation (e.g., 93, 94). Some researchers have even reported the opposite of the “expected” relation, that TBI increases the risk for Alzheimer’s disease in those without the genetic characteristic (e.g., 87, 88, 96). Thus, the role of ApoE in the relation between TBI and Alzheimer’s disease requires further study.

Mortimer and colleagues conducted an important meta-analytic review of the entire literature published prior to 1991 (116). They reported that traumatic brain injuries were associated with a 1.82 relative risk (RR) (95% confidence interval = 1.26 to 2.67) for developing Alzheimer’s disease. The relative risk was significant for men (RR = 2.67, 95% CI = 1.64 to 4.41) but not for women (RR = 0.85, 95% CI = 0.43 to 1.70). This meta-analysis, and the individual studies reporting the connection, have slowly lead to a widespread clinical belief that TBI increases a patient’s risk for Alzheimer’s disease. By extension, clinicians have assumed that mild TBI also increases the risk, even though most of the literature is based on moderate or severe TBIs. However, Fleminger and colleagues conducted a second meta-analytic review of the literature and reported that studies publishedsince 1991 did not reveal a statistically significant increased risk for Alzheimer’s disease (117). Fleminger and colleagues reported that if one considers the entire literature (i.e., the studies published before and after the Mortimer meta-analysis) there is an increased risk for Alzheimer’s disease associated with a history of TBI (Odds Ratio (OR) = 1.58, 95% CI = 1.21 to 2.06). This increased risk was significant for men (OR = 2.26, 95% CI = 1.13 to 4.53) but not for women (OR = 0.92, 95% CI = 0.53 to 1.59). Starkstein and Jorge (118) suggested that this increased risk in men and not women might simply reflect men sustaining more severe traumatic brain injuries. Jellinger, in his review of the literature, concluded that the epidemiological and autopsy studies have provided evidence of an association between severe traumatic brain injury and Alzheimer’s disease (86).

 

Conclusions

Mild traumatic brain injuries are heterogeneous and highly individualized injuries. Recovery and return to pre-injury functioning is influenced by numerous factors. Nonetheless, the cognitive and neurobehavioral consequences of the injury are self-limiting and reasonably predictable. MTBIs are characterized by immediate physiological changes conceptualized as a multilayered neurometabolic cascade in which affected cells typically recover, although under certain circumstances a small number might degenerate and die. The primary pathophysiologies include ionic shifts, abnormal energy metabolism, diminished cerebral blood flow, and impaired neurotransmission.

It is important to appreciate that cell death is closely related to injury severity. Mild traumatic brain injuries, especially injuries on the milder end of the spectrum, are typically characterized by cellular dysfunction that is reversible. There is a continuum of injury, at the cellular level, ranging from completely and rapidly reversible cellular dysfunction, to slow but complete recovery, to slow and incomplete recovery, to cell death. Very mild concussions likely produce virtually no permanent damage to cells resulting in long-term symptoms or problems whereas severe traumatic brain injuries, especially those involving considerable forces, often produce widespread cellular death and dysfunction with clear functional consequences; complicated MTBIs and moderate TBIs likely fall in between.

In patients with MTBIs, the brain undergoes dynamic restoration in the first two weeks post injury. The patient typically experiences maximal symptoms and problems within the first 72 hours with rapid improvement in functioning over the first two weeks. Athletes typically report resolution of symptoms within 2-21 days. Trauma patients typically take longer to return to their baseline functioning, but most recover within three months post injury. Some take considerably longer to recover. This can be due to a variety of factors, only some of which relate to the actual injury to the brain. Permanent damage to the brain occurs in some patients who sustain MTBIs, but the majority of the pathophysiology is neurometabolic and reversible.

In regards to risk for Alzheimer’s disease, there are many conflicting results in this large literature spanning more than 20 years. Nonetheless, it is reasonable to conclude that patients who sustain severe TBIs are at a small increased risk for the future development of Alzheimer’s disease, as concluded by Starkstein and Jorge (118) and Jellinger (86). Given that (a) many studies have failed to find an association between history of TBI (of any severity) and the disease, (b) the meta-analyses have only identified this association for men, (c) several studies have found a severity effect (i.e., risk is greater in patients with more severe brain injuries), and (d) the pathophysiology of MTBI, especially on the milder end of the spectrum of this injury, appears to be temporary and reversible, it would be a mistake to conclude, at this point in time, that patients with MTBIs, as a group, are at increased risk for Alzheimer’s disease. Several specific studies suggest that there is not a relationship between MTBI and risk for Alzheimer’s disease (e.g., 94, 98, 109).

 


It is important to note that the decreases in cerebral blood flow (CBF) do not reach ischemic levels. These are mild reductions and certainly not serious alterations in CBF with the additional vascular complications often seen in patients with moderate to severe brain injuries (49).

Animal studies are underway examining the influence of treatment with magnesium on outcome from TBI (50).

Grant L. Iverson, Ph.D., Professor 
Faculty of Medicine, Department of Psychiatry 
The University of British Columbia 
Senior Researcher 
British Columbia Mental Health & Addiction Services 
University Phone: (604) 822-7588 
Hospital Phone: (604) 524-7567 
Best Email: giverson@interchange.ubc.ca

References

  1. Corrada M, Brookmeyer R, Kawas C. Sources of variability in prevalence rates of Alzheimer's disease. Int J Epidemiol 1995;24:1000-1005.
  2. Jorm AF, Korten AE, Henderson AS. The prevalence of dementia: a quantitative integration of the literature. Acta Psychiatr Scand 1987;76:465-479.
  3. Hofman A, Rocca WA, Brayne C, Breteler MM, Clarke M, Cooper B, Copeland JR, Dartigues JF, da Silva Droux A, Hagnell O, et al. The prevalence of dementia in Europe: a collaborative study of 1980-1990 findings. Eurodem Prevalence Research Group. Int J Epidemiol 1991;20:736-748.
  4. Rocca WA, Hofman A, Brayne C, Breteler MM, Clarke M, Copeland JR, Dartigues JF, Engedal K, Hagnell O, Heeren TJ, et al. Frequency and distribution of Alzheimer's disease in Europe: a collaborative study of 1980-1990 prevalence findings. The EURODEM-Prevalence Research Group. Ann Neurol 1991;30:381-390.
  5. Lahiri DK. Apolipoprotein E as a target for developing new therapeutics for Alzheimer's disease based on studies from protein, RNA, and regulatory region of the gene. J Mol Neurosci 2004;23:225-233.
  6. Nielsen AS, Ravid R, Kamphorst W, Jorgensen OS. Apolipoprotein E epsilon 4 in an autopsy series of various dementing disorders. J Alzheimers Dis 2003;5:119-125.
  7. St George-Hyslop PH, Petit A. Molecular biology and genetics of Alzheimer's disease. C R Biol2005;328:119-130.
  8. Heininger K. A unifying hypothesis of Alzheimer's disease. III. Risk factors. Hum Psychopharmacol2000;15:1-70.
  9. Korf ES, Scheltens P, Barkhof F, de Leeuw FE. Blood Pressure, White Matter Lesions and Medial Temporal Lobe Atrophy: Closing the Gap between Vascular Pathology and Alzheimer's Disease? Dement Geriatr Cogn Disord 2005;20:331-337.
  10. Decarli C. Vascular factors in dementia: an overview. J Neurol Sci 2004;226:19-23.
  11. Newman AB, Fitzpatrick AL, Lopez O, Jackson S, Lyketsos C, Jagust W, Ives D, Dekosky ST, Kuller LH. Dementia and Alzheimer's disease incidence in relationship to cardiovascular disease in the Cardiovascular Health Study cohort. J Am Geriatr Soc 2005;53:1101-1107.
  12. Sjogren M, Blennow K. The link between cholesterol and Alzheimer's disease. World J Biol Psychiatry2005;6:85-97.
  13. Ravaglia G, Forti P, Maioli F, Martelli M, Servadei L, Brunetti N, Porcellini E, Licastro F. Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr 2005;82:636-643.
  14. Luchsinger JA, Reitz C, Honig LS, Tang MX, Shea S, Mayeux R. Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology 2005;65:545-551.
  15. Calabrese V, Butterfield DA, Stella AM. Nutritional antioxidants and the heme oxygenase pathway of stress tolerance: novel targets for neuroprotection in Alzheimer's disease. Ital J Biochem 2003;52:177-181.
  16. Calabrese V, Scapagnini G, Colombrita C, Ravagna A, Pennisi G, Giuffrida Stella AM, Galli F, Butterfield DA. Redox regulation of heat shock protein expression in aging and neurodegenerative disorders associated with oxidative stress: a nutritional approach. Amino Acids 2003;25:437-444.
  17. Mocchegiani E, Bertoni-Freddari C, Marcellini F, Malavolta M. Brain, aging and neurodegeneration: role of zinc ion availability. Prog Neurobiol 2005;75:367-390.
  18. Streit WJ. Microglia and neuroprotection: implications for Alzheimer's disease. Brain Res Brain Res Rev2005;48:234-239.
  19. Srinivasan V, Pandi-Perumal SR, Maestroni GJ, Esquifino AI, Hardeland R, Cardinali DP. Role of melatonin in neurodegenerative diseases. Neurotox Res 2005;7:293-318.
  20. Treiber C. Metals on the brain. Sci Aging Knowledge Environ 2005;2005:pe27.
  21. Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kareholt I, Winblad B, Helkala EL, Tuomilehto J, Soininen H, Nissinen A. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease.Arch Neurol 2005;62:1556-1560.
  22. Kiraly MA, Kiraly SJ. The effect of exercise on hippocampal integrity: review of recent research. Int J Psychiatry Med 2005;35:75-89.
  23. Lindstrom HA, Fritsch T, Petot G, Smyth KA, Chen CH, Debanne SM, Lerner AJ, Friedland RP. The relationships between television viewing in midlife and the development of Alzheimer's disease in a case-control study. Brain Cogn 2005;58:157-165.
  24. Beeri MS, Davidson M, Silverman JM, Noy S, Schmeidler J, Goldbourt U. Relationship between body height and dementia. Am J Geriatr Psychiatry 2005;13:116-123.
  25. Andersen K, Lolk A, Kragh-Sorensen P, Petersen NE, Green A. Depression and the risk of Alzheimer disease. Epidemiology 2005;16:233-238.
  26. Dal Forno G, Palermo MT, Donohue JE, Karagiozis H, Zonderman AB, Kawas CH. Depressive symptoms, sex, and risk for Alzheimer's disease. Ann Neurol 2005;57:381-387.
  27. Carroll LJ, Cassidy JD, Peloso PM, Borg J, von Holst H, Holm L, Paniak C, Pépin M. Prognosis for mild traumatic brain injury: Results of the WHO collaborating centre task force on mild traumatic brain injury. J Rehabil Med 2004;36:84-105.
  28. Peloso PM, Carroll LJ, Cassidy JD, Borg J, von Holst H, Holm L, Yates D. Critical evaluation of the existing guidelines on mild traumatic brain injury. J Rehabil Med 2004:106-112.
  29. Borg J, Holm L, Peloso PM, Cassidy JD, Carroll LJ, von Holst H, Paniak C, Yates D. Non-surgical intervention and cost for mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. J Rehabil Med 2004:76-83.
  30. Borg J, Holm L, Cassidy JD, Peloso PM, Carroll LJ, von Holst H, Ericson K. Diagnostic procedures in mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury.J Rehabil Med 2004:61-75.
  31. Cassidy JD, Carroll LJ, Peloso PM, Borg J, von Holst H, Holm L, Kraus J, Coronado VG. Incidence, risk factors and prevention of mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. J Rehabil Med 2004:28-60.
  32. Carroll LJ, Cassidy JD, Holm L, Kraus J, Coronado VG. Methodological issues and research recommendations for mild traumatic brain injury: the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. J Rehabil Med 2004:113-125.
  33. Mild Traumatic Brain Injury Committee ACoRM, Head Injury Interdisciplinary Special Interest Group. Definition of mild traumatic brain injury. J Head Trauma Rehabil 1993;8:86-87.
  34. National Center for Injury Prevention and Control. Report to congress on mild traumatic brain injury in the United States: Steps to prevent a serious public health problem. Atlanta, GA: Centers for Disease Control and Prevention, 2003.
  35. Berube J. The Traumatic Brain Injury Act Amendments of 2000. J Head Trauma Rehabil 2001;16:210-213.
  36. Center for Disease Control and Prevention. Traumatic brain injury in the United States: a report to Congress. Volume 2005, 2003.
  37. National Institutes of Health. Rehabilitation of persons with traumatic brain injury. NIH Consens Statement1998;16:1-41.
  38. McCrea M, Hammeke T, Olsen G, Leo P, Guskiewicz K. Unreported concussion in high school football players: implications for prevention. Clin J Sport Med 2004;14:13-17.
  39. Sosin DM, Sniezek JE, Thurman DJ. Incidence of mild and moderate brain injury in the United States, 1991. Brain Inj 1996;10:47-54.
  40. Bazarian JJ, McClung J, Cheng YT, Flesher W, Schneider SM. Emergency department management of mild traumatic brain injury in the USA. Emerg Med J 2005;22:473-477.
  41. French BN, Dublin AB. The value of computerized tomography in the management of 1000 consecutive head injuries. Surg Neurol 1977;7:171-183.
  42. Iverson GL, Lovell MR, Smith S, Franzen MD. Prevalence of abnormal CT-scans following mild head injury. Brain Inj 2000;14:1057-1061.
  43. Jeret JS, Mandell M, Anziska B, Lipitz M, Vilceus AP, Ware JA, Zesiewicz TA. Clinical predictors of abnormality disclosed by computed tomography after mild head trauma. Neurosurgery 1993;32:9-15; discussion 15-16.
  44. Livingston DH, Loder PA, Koziol J, Hunt CD. The use of CT scanning to triage patients requiring admission following minimal head injury. J Trauma 1991;31:483-487; discussion 487-489.
  45. Levin HS, Williams DH, Eisenberg HM, High WM, Jr., Guinto FC, Jr. Serial MRI and neurobehavioural findings after mild to moderate closed head injury. J Neurol Neurosurg Psychiatry 1992;55:255-262.
  46. Tellier A, Della Malva LC, Cwinn A, Grahovac S, Morrish W, Brennan-Barnes M. Mild head injury: a misnomer. Brain Inj 1999;13:463-475.
  47. Bigler ED. Neuropsychological results and neuropathological findings at autopsy in a case of mild traumatic brain injury. J Int Neuropsychol Soc 2004;10:794-806.
  48. Giza CC, Hovda DA. The pathophysiology of traumatic brain injury. In: Lovell MR, Echemendia RJ, Barth JT, Collins MW, editors. Traumatic Brain Injury in Sports. Lisse: Swets & Zeitlinger, 2004. p 45-70.
  49. DeWitt DS, Prough DS. Traumatic cerebral vascular injury: the effects of concussive brain injury on the cerebral vasculature. J Neurotrauma 2003;20:795-825.
  50. Lee JS, Han YM, Yoo do S, Choi SJ, Choi BH, Kim JH, Kim YH, Huh PW, Ko YJ, Rha HK, Cho KS, Kim DS. A molecular basis for the efficacy of magnesium treatment following traumatic brain injury in rats. J Neurotrauma 2004;21:549-561.
  51. Raghupathi R, Conti AC, Graham DI, Krajewski S, Reed JC, Grady MS, Trojanowski JQ, McIntosh TK. Mild traumatic brain injury induces apoptotic cell death in the cortex that is preceded by decreases in cellular Bcl-2 immunoreactivity. Neuroscience 2002;110:605-616.
  52. Raghupathi R. Cell death mechanisms following traumatic brain injury. Brain Pathol 2004;14:215-222.
  53. Belanger HG, Vanderploeg RD. The neuropsychological impact of sports-related concussion: A meta-analysis. J Int Neuropsychol Soc 2005;11:345-357.
  54. Belanger HG, Curtiss G, Demery JA, Lebowitz BK, Vanderploeg RD. Factors moderating neuropsychological outcomes following mild traumatic brain injury: a meta-analysis. J Int Neuropsychol Soc 2005;11:215-227.
  55. Iverson GL. Outcome from mild traumatic brain injury. Curr Opin Psychiat 2005;18:301-317.
  56. Schretlen DJ, Shapiro AM. A quantitative review of the effects of traumatic brain injury on cognitive functioning. Int Rev Psychiatry 2003;15:341-349.
  57. Rees PM. Contemporary issues in mild traumatic brain injury. Arch Phys Med Rehabil 2003;84:1885-1894.
  58. Iverson GL, Zasler ND, Lange RT. Post-Concussive disorders. In: Zasler ND, Katz HT, Zafonte RD, editors.Brain Injury Medicine: Principles and Practice. New York: Demos Medical Publishing, 2006. p 373-405.
  59. Fenton G, McClelland R, Montgomery A, MacFlynn G, Rutherford W. The postconcussional syndrome: social antecedents and psychological sequelae. Br J Psychiatry 1993;162:493-497.
  60. Ponsford J, Willmott C, Rothwell A, Cameron P, Kelly AM, Nelms R, Curran C, Ng K. Factors influencing outcome following mild traumatic brain injury in adults. J Int Neuropsychol Soc 2000;6:568-579.
  61. Evered L, Ruff R, Baldo J, Isomura A. Emotional risk factors and postconcussional disorder. Assessment2003;10:420-427.
  62. McCauley SR, Boake C, Levin HS, Contant CF, Song JX. Postconcussional disorder following mild to moderate traumatic brain injury: anxiety, depression, and social support as risk factors and comorbidities. J Clin Exp Neuropsychol 2001;23:792-808.
  63. Karzmark P, Hall K, Englander J. Late-onset post-concussion symptoms after mild brain injury: the role of premorbid, injury-related, environmental, and personality factors. Brain Inj 1995;9:21-26.
  64. Gasquoine PG. Postconcussional symptoms in chronic back pain. Appl Neuropsychol 2000;7:83-89.
  65. Iverson GL, McCracken LM. 'Postconcussive' symptoms in persons with chronic pain. Brain Inj1997;11:783-790.
  66. Smith-Seemiller L, Fow NR, Kant R, Franzen MD. Presence of post-concussion syndrome symptoms in patients with chronic pain vs mild traumatic brain injury. Brain Inj 2003;17:199-206.
  67. Gunstad J, Suhr JA. Cognitive factors in Postconcussion Syndrome symptom report. Arch Clin Neuropsychol 2004;19:391-405.
  68. Wilde EA, Bigler ED, Gandhi PV, Lowry CM, Blatter DD, Brooks J, Ryser DK. Alcohol abuse and traumatic brain injury: quantitative magnetic resonance imaging and neuropsychological outcome. J Neurotrauma2004;21:137-147.
  69. Paniak C, Reynolds S, Toller-Lobe G, Melnyk A, Nagy J, Schmidt D. A longitudinal study of the relationship between financial compensation and symptoms after treated mild traumatic brain injury. J Clin Exp Neuropsychol 2002;24:187-193.
  70. Feinstein A, Ouchterlony D, Somerville J, Jardine A. The effects of litigation on symptom expression: a prospective study following mild traumatic brain injury. Med Sci Law 2001;41:116-121.
  71. Reynolds S, Paniak C, Toller-Lobe G, Nagy J. A longitudinal study of compensation-seeking and return to work in a treated mild traumatic brain injury sample. J Head Trauma Rehabil 2003;18:139-147.
  72. Martin RC, Hayes JS, Gouvier WD. Differential vulnerability between postconcussion self-report and objective malingering tests in identifying simulated mild head injury. J Clin Exp Neuropsychol1996;18:265-275.
  73. Greiffenstein MF, Baker WJ, Gola T, Donders J, Miller L. The fake bad scale in atypical and severe closed head injury litigants. J Clin Psychol 2002;58:1591-1600.
  74. Ross SR, Millis SR, Krukowski RA, Putnam SH, Adams KM. Detecting incomplete effort on the MMPI-2: an examination of the Fake-Bad Scale in mild head injury. J Clin Exp Neuropsychol 2004;26:115-124.
  75. Larrabee GJ. Exaggerated MMPI-2 symptom report in personal injury litigants with malingered neurocognitive deficit. Arch Clin Neuropsychol 2003;18:673-686.
  76. Mittenberg W, Patton C, Canyock EM, Condit DC. Base rates of malingering and symptom exaggeration. J Clin Exp Neuropsychol 2002;24:1094-1102.
  77. Mittenberg W, DiGiulio DV, Perrin S, Bass AE. Symptoms following mild head injury: Expectation as aetiology. J Neurol Neurosurg Psychiatry 1992;55:200-204.
  78. Ferguson RJ, Mittenberg W, Barone DF, Schneider B. Postconcussion syndrome following sports-related head injury: expectation as etiology. Neuropsychology 1999;13:582-589.
  79. Gunstad J, Suhr JA. Perception of illness: nonspecificity of postconcussion syndrome symptom expectation. J Int Neuropsychol Soc 2002;8:37-47.
  80. Ferrari R, Obelieniene D, Russell AS, Darlington P, Gervais R, Green P. Symptom expectation after minor head injury. A comparative study between Canada and Lithuania. Clin Neurol Neurosurg 2001;103:184-190.
  81. Gunstad J, Suhr JA. "Expectation as etiology" versus "the good old days": postconcussion syndrome symptom reporting in athletes, headache sufferers, and depressed individuals. J Int Neuropsychol Soc2001;7:323-333.
  82. Davis CH. Self-perception in mild traumatic brain injury. Am J Phys Med Rehabil 2002;81:609-621.
  83. Lees-Haley PR, Williams CW, Zasler ND, Marguilies S, English LT, Stevens KB. Response bias in plaintiffs' histories. Brain Inj 1997;11:791-799.
  84. Lye TC, Shores EA. Traumatic brain injury as a risk factor for Alzheimer's disease: a review. Neuropsychol Rev 2000;10:115-129.
  85. Szczygielski J, Mautes A, Steudel WI, Falkai P, Bayer TA, Wirths O. Traumatic brain injury: cause or risk of Alzheimer's disease? A review of experimental studies. J Neural Transm 2005;112:1547-1564.
  86. Jellinger KA. Head injury and dementia. Curr Opin Neurol 2004;17:719-723.
  87. 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;8:707-710.
  88. 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;1:3.
  89. Canadian Study of Health and Aging. The Canadian Study of Health and Aging: risk factors for Alzheimer's disease in Canada. Neurology 1994;44:2073-2080.
  90. van Duijn CM, Tanja TA, Haaxma R, Schulte W, Saan RJ, Lameris AJ, Antonides-Hendriks G, Hofman A. Head trauma and the risk of Alzheimer's disease. Am J Epidemiol 1992;135:775-782.
  91. Salib E, Hillier V. Head injury and the risk of Alzheimer's disease: a case control study. Int J Geriatr Psychiatry 1997;12:363-368.
  92. Graves AB, White KP, Koepsell TD, Reifler BV, van Belle G, Larson EB, Raskind M. The association between head trauma and Alzheimer's disease. Am J Epidemiol 1990;131:491-501.
  93. O'Meara ES, Kukull WA, Sheppard L, Bowen JD, McCormick WC, Teri L, Pfanschmidt M, Thompson JD, Schellenberg GD, Larson EB. Head injury and risk of Alzheimer's disease by apolipoprotein E genotype.Am J Epidemiol 1997;146:373-384.
  94. 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;55:1158-1166.
  95. Chandra V, Philipose V, Bell PA, Lazaroff A, Schoenberg BS. Case-control study of late onset "probable Alzheimer's disease". Neurology 1987;37:1295-1300.
  96. Guo Z, Cupples LA, Kurz A, Auerbach SH, Volicer L, Chui H, Green RC, Sadovnick AD, Duara R, DeCarli C, Johnson K, Go RC, Growdon JH, Haines JL, Kukull WA, Farrer LA. Head injury and the risk of AD in the MIRAGE study. Neurology 2000;54:1316-1323.
  97. Luukinen H, Viramo P, Herala M, Kervinen K, Kesaniemi YA, Savola O, Winqvist S, Jokelainen J, Hillbom M. Fall-related brain injuries and the risk of dementia in elderly people: a population-based study. Eur J Neurol 2005;12:86-92.
  98. Luukinen H, Viramo P, Koski K, Laippala P, Kivela SL. Head injuries and cognitive decline among older adults: a population-based study. Neurology 1999;52:557-562.
  99. Rasmussen DX, Brandt J, Martin DB, Folstein MF. Head injury as a risk factor in Alzheimer's disease. Brain Inj 1995;9:213-219.
  100. Mayeux R, Ottman R, Tang MX, Noboa-Bauza L, Marder K, Gurland B, Stern Y. Genetic susceptibility and head injury as risk factors for Alzheimer's disease among community-dwelling elderly persons and their first-degree relatives. Ann Neurol 1993;33:494-501.
  101. Schofield PW, Tang M, Marder K, Bell K, Dooneief G, Chun M, Sano M, Stern Y, Mayeux R. Alzheimer's disease after remote head injury: an incidence study. J Neurol Neurosurg Psychiatry 1997;62:119-124.
  102. Mortimer JA, French LR, Hutton JT, Schuman LM. Head injury as a risk factor for Alzheimer's disease.Neurology 1985;35:264-267.
  103. Amaducci LA, Fratiglioni L, Rocca WA, Fieschi C, Livrea P, Pedone D, Bracco L, Lippi A, Gandolfo C, Bino G, et al. Risk factors for clinically diagnosed Alzheimer's disease: a case-control study of an Italian population. Neurology 1986;36:922-931.
  104. Ferini-Strambi L, Smirne S, Garancini P, Pinto P, Franceschi M. Clinical and epidemiological aspects of Alzheimer's disease with presenile onset: a case control study. Neuroepidemiology 1990;9:39-49.
  105. Fratiglioni L, Ahlbom A, Viitanen M, Winblad B. Risk factors for late-onset Alzheimer's disease: a population-based, case-control study. Ann Neurol 1993;33:258-266.
  106. Nemetz PN, Leibson C, Naessens JM, Beard M, Kokmen E, Annegers JF, Kurland LT. Traumatic brain injury and time to onset of Alzheimer's disease: a population-based study. Am J Epidemiol 1999;149:32-40.
  107. Katzman R, Aronson M, Fuld P, Kawas C, Brown T, Morgenstern H, Frishman W, Gidez L, Eder H, Ooi WL. Development of dementing illnesses in an 80-year-old volunteer cohort. Ann Neurol 1989;25:317-324.
  108. Li G, Shen YC, Li YT, Chen CH, Zhau YW, Silverman JM. A case-control study of Alzheimer's disease in China. Neurology 1992;42:1481-1488.
  109. Mehta KM, Ott A, Kalmijn S, Slooter AJ, van Duijn CM, Hofman A, Breteler MM. Head trauma and risk of dementia and Alzheimer's disease: The Rotterdam Study. Neurology 1999;53:1959-1962.
  110. Chandra V, Kokmen E, Schoenberg BS, Beard CM. Head trauma with loss of consciousness as a risk factor for Alzheimer's disease. Neurology 1989;39:1576-1578.
  111. Broe GA, Henderson AS, Creasey H, McCusker E, Korten AE, Jorm AF, Longley W, Anthony JC. A case-control study of Alzheimer's disease in Australia. Neurology 1990;40:1698-1707.
  112. Waters RJ, Nicoll JA. Genetic influences on outcome following acute neurological insults. Curr Opin Crit Care 2005;11:105-110.
  113. Nathoo N, Chetty R, van Dellen JR, Barnett GH. Genetic vulnerability following traumatic brain injury: the role of apolipoprotein E. Mol Pathol 2003;56:132-136.
  114. 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;45:555-557.
  115. Koponen S, Taiminen T, Kairisto V, Portin R, Isoniemi H, Hinkka S, Tenovuo O. APOE-epsilon4 predicts dementia but not other psychiatric disorders after traumatic brain injury. Neurology 2004;63:749-750.
  116. Mortimer JA, van Duijn CM, Chandra V, Fratiglioni L, Graves AB, Heyman A, Jorm AF, Kokmen E, Kondo K, Rocca WA, et al. 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.
  117. 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;74:857-862.
  118. Starkstein SE, Jorge R. Dementia after traumatic brain injury. Int Psychogeriatr 2005;17 Suppl 1:S93-107.